Novel cyclosporin galenic forms

ABSTRACT

Pharmaceutical compositions comprising a cyclosporin as active ingredient, a fatty acid triglyceride, a glycerol fatty acid partial ester or propylene glycol or sorbitol complete or partial ester, preferably, and a tenside having an HLB of at least 10.

[0001] The present application is a continuation-in-part of U.S.application Ser. No. 07/462,373, filed Jan. 9, 1990, currently pending,which in turn was a continuation of U.S. application Ser. No.07/373,736, filed Jun. 29, 1989, now abandoned, which in turn was acontinuation of U.S. application Ser. No. 07/193,986, filed May 13,1988, now abandoned, which in turn was a continuation of US ApplicationSer. No. 06/901 356 filed Aug. 28, 1986, now abandoned, which in turnwas a continuation of US Application Ser. No. 06/633 808, filed Jul. 24,1984, now abandoned.

[0002] The present invention relates to novel galenic formulations, inparticular novel pharmaceutical compositions as well a novel oral dosageforms comprising a cyclosporin as active ingredient.

[0003] The cyclosporins comprise a class of structurally distinctive,cyclic, poly-N-methylated endecapeptides, commonly possessingpharmacological, in particular immunosuppressive, anti-inflammatoryand/or anti-parasitic (in particular anti-protozoal, e.g. anti-malarial)activity. The first of the cyclosporins to be isolated was the naturallyoccurring fungal metabolite Ciclosporin or Cyclosporine, also known ascyclosporin A and commercially available under the Registered Trade MarkSANDIMMUNR or SANDIMMUNER. Ciclosporin is the cyclosporin of formula A.

[0004] wherein -MeBmt- represents the N-methyl-(4 R)-4-but-2E-en-1-yl-4-methyl-(L)threonyl residue of formula B

[0005] in which -x-y- is —CH═CH— (trans).

[0006] As the parent of the class Ciclosporin has so far received themost attention. The primary area of clinical investigation forCiclosporin has been as an immunosuppressive agent, in particular inrelation to its application to recipients of organ transplants, e.g.heart, lung, combined heart-lung, liver, kidney, pancreatic,bone-marrow, skin and corneal transplants and, in particular, allogenicorgan transplants. In this field Ciclosporin has achieved a remarkablesuccess and reputation.

[0007] At the same time, applicability of Ciclosporin to variousautoimmune diseases and to inflammatory conditions, in particularinflammatory conditions with an aetiology including an autoimmunecomponent such as arthritis (for example rheumatoid arthritis, arthritischronica progrediente and arthritis deformans) and rheumatic diseases,has been intensive and reports and results in vitro, in animal modelsand in clinical trials are wide-spread in the literature. Specificauto-immune diseases for which Ciclosporin therapy has been proposed orapplied include, autoimmune hematological disorder (including e.g.hemolytic anaemia, aplastic anaemia, pure red cell anaemia andidiopathic thrombocytopaenia), systemic lupus erythematosus,polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis,chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnsonsyndrome, idiopathic sprue, autoimmune inflammatory bowel disease(including e.g. ulcerative colitis and Crohn's disease) endocrineopthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primarybilliary cirrhosis, juvenile diabetes (diabetes mellitus type I),uveitis (anterior and posterior), keratoconjunctivitis sicca and vernalkeratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritisand glomerulonephritis (with and without nephrotic syndrome, e.g.including idiopathic nephrotic syndrome or minimal change nephropathy).

[0008] Further areas of investigation have been potential applicabilityas an anti-parasitic, in particular anti-protozoal agent, with possibleuses suggested including treatment of malaria, coccidiomycosis andschistosomiasis and, yet more recently, use in cancer therapy, e.g. asan agent for reversing or abrogating resistance to other anti-neoplasticor cytostatic therapy.

[0009] Since the original discovery of ciclosporin, a wide variety ofnaturally occurring cyclosporins have been isolated and identified andmany further non-natural cyclosporins have been prepared by total- orsemi-synthetic means or by the application of modified culturetechniques. The class comprised by the cyclosporins is thus nowsubstantial and includes, for example, the naturally occurringcyclosporins A through Z [c.f. Traber et al. 1, Helv. Chim. Acta. 60,1247-1255 (1977); Traber et al. 2, Helv. Chim. Acta. 65 no. 162,1655-1667 (1982); Kobel et al., Europ. J. Applied Microbiology andBiotechnology 14, 273-240 (1982); and von Wartburg et al., Progress inAllergy, 38, 28-45 (1986)], as well as various non-natural cyclosporinderivatives and artificial or synthetic cyclosporins including the socalled dihydro-cyclosporins [in which the moiety -x-y- of the -MeBmt-residue (Formula B above) is saturated to give -x-y-=—CH₂—CH₂—];derivatised cyclosporins (e.g. in which a further substituent isintroduced at the α-carbon atom of the sarcosyl residue at the3-position of the cyclosporin molecule); cyclosporins in which the-MeBmt- residue is present in isomeric form (e.g. in which theconfiguration across positions 6′ and 7′ of the -MeBmt- residue is cisrather than trans); and cyclosporins wherein variant amino acids areincorporated at specific positions within the peptide sequence,employing e.g. the total synthetic method for the production ofcyclosporins developed by R. Wenger—see e.g. Traber 1, Traber 2 andKobel loc. cit.; U.S. Pat. Nos. 4,108,985, 4,210,581 and 4,220,641;European Patent Publication Nos. 0 034 567, 0 056 782 and 0 296 122;International Patent Publication No. WO 86/02080; Wenger 1, Transp.Proc. 15, Suppl. 1:2230 (1983); Wenger 2, Angew. Chem. Int. Ed., 24, 77(1985); and Wenger 3, Progress in the Chemistry of Organic NaturalProducts 50, 123 (1986).

[0010] The class comprised by the cyclosporins thus now includes, forexample, [Thr]²-, [Val]²-, [Nva]²- and [Nva]²-[Nva]⁵-Ciclosporin (alsoknown as cyclosporins C, D, G and M respectively),[3′-O-acyl-MeBmt]¹-Ciclosporin (also known as cyclosporin A acetate),[Dihydro-MeBmt]¹-[Val]²-Ciclosporin (also known as dihydro-cyclosporinD), (3′-Desoxy-3′-oxo-MeBmt]¹[Val]²- and -[Nva]²-Ciclosporin,[(D)Fluoromethyl-Sar]3-Ciclosporin, [(D)Ser]³-Ciclosporin,[MeIle]¹¹-Ciclosporin, [(D)MeVal]¹¹-Ciclosporin (also known ascyclosporin H), [MeAla]⁶-Ciclosporin, [(D)Pro]³-Ciclosporin and so on.

[0011] [In accordance with now conventional nomenclature forcyclosporins, these are defined by reference to the structure ofCiclosporin (i.e. Cyclosporin A). This is done by first indicating theamino acid residues present which differ from those present inCiclosporin (e.g. “[(D)Pro]³” to indicate that the cyclosporin inquestion has a -(D)Pro- rather than -Sar- residue at the 3-position) andthen applying the term “Ciclosporin” to characterise remaining residueswhich are identical to those present in Ciclosporin. Individual residuesare numbered starting with the residue -MeBmt-, -dihydro-MeBmt- or itsequivalent in position 1.]

[0012] Very many of these further cyclosporins exhibit comparablepharmaceutical utility to Ciclosporin or more specific utility, forexample activity particularly in reversing tumor resistance tocytostatic therapy, and proposals for their application as therapeuticagents abound in the literature.

[0013] Despite the major contribution which Ciclosporin has made, inparticular to the areas of organ transplant and the therapy ofautoimmune diseases, difficulties encountered in providing moreeffective and convenient means of administration (e.g. galenicformulations, for example oral dosage forms, which are both convenientfor the patient as well as providing appropriate bio-availability andallowing dosaging at an appropriate and controlled dosage rate) as wellas the reported occurrence of undesirable side reactions, in particularnephrotoxic reaction, have been obvious serious impediments to its wideruse or application.

[0014] The cyclosporins are characteristically highly hydrophobic andreadily precipitate in the presence of even very minor amounts of water,e.g. on contact with the body (e.g. stomach) fluids. It is accordinglyextremely difficult to provide, e.g. oral formulations which areacceptable to the patient in terms of form and taste, which are stableon storage and which can be administered on a regular basis to providesuitable and controllable patient dosaging.

[0015] Proposed liquid formulations, e.g. for oral administration ofcyclosporins, have hitherto been based on the use of oils in conjunctionwith solvent systems comprising, e.g. ethanol and Labrafils andequivalent excipients as carrier media. Thus the commercially availableCiclosporin drink-solution employs ethanol and olive oil or corn-oil ascarrier medium in conjunction with a Labrafil as co-solvent—see e.g.U.S. Pat. No. 4,388,307. Use of the drink-solution and similarcompositions as proposed in the art is however accompanied by a varietyof difficulties.

[0016] First the palatability of the known oil based systems has provedproblematic. The taste of the known drink-solution is, in particualr,unpleasant and admixture with an appropriate flavoured drink, forexample chocolate drink preparation, at high dilution immediately priorto ingestion has generally been practiced in order to make regulartherapy at all acceptable. Adoption of oil based systems hitherto hasalso required the use of high ethanol concentrations to maintainsolubility. Use of ethanol is in itself inherently undesirable, inparticular where administration to children is foreseen. In addition,evaporation of the ethanol, e.g. from encapsulated forms (adopted, inlarge part, to meet problems of palatibility as discussed above), orother forms (e.g. when opened) results in development of a precipitate.Where such compositions are presented in e.g. soft gelatin encapsulatedform, this particular difficulty necessitates packaging of theencapsulated product in an air-tight compartment, for example anair-tight blister or aluminium-foil blister package or container. Thisin turn renders the product both bulky and more expensive to produce.The storage characteristics of such formulations are thus far fromideal.

[0017] Use of such dosage forms is also characterised by extremevariation in required patient dosaging. In order to achieve effectiveimmunosuppressive therapy, cyclosporin blood or blood serum levels haveto be maintained within in a specified range. This range in turn canvary, depending on the particular condition being treated, e.g. whethertherapy is to prevent transplant rejection or for the control of anautoimmune disease or condition, and on whether or not alternativeimmunosuppressive therapy is employed concomitantly with cyclosporintherapy. Experience shows however that, e.g. employing the availableCiclosporin drink solution, daily dosages needed to achieve requiredblood serum levels vary considerably from individual to individual andeven for a single individual at different times. For this reason it isnecessary to monitor blood/blood-serum levels of patients receivingCiclosporin therapy at regular and frequent intervals in order that thedaily dosage taken may be adjusted to maintain blood/blood-serum levelswithin the required range. Monitoring of blood/blood-serum levels, whichis generally performed by RIA or equivalent immunoassay technique, e.g.employing monoclonal antibody based technology, has to be carried outfor each patient receiving Ciclosporin therapy on a regular basis. Thisis inevitably time consuming and inconvenient and adds substantially tothe overall cost of therapy.

[0018] It is also the case that blood/blood-serum cyclosporin levelsachieved using available dosage systems exhibit extreme variationbetween peak and trough levels. That is, for each patient, effectivecyclosporin levels in the blood vary widely between administration ofindividual dosages. This variation in patient response has been found tobe attributable to a significant extent to variation in the availabilityof naturally occurring surfactant components, e.g. bile acids and salts,within the gastro-intestinal tract of the subject treated. For galenicformulations for cyclosporins hitherto known in the art, the presence ofsuch natural surfactants in sufficient quantity is required ifsatisfactory resorption is to be achieved. However the availability ofsuch surfactants in the gastro-intestinal tract inevitably varies fromsubject to subject and in individual subjects with time.

[0019] Apart from the unsatisfactory nature of such inconsistancy intherapy, this also means that individual patients must be monitored oneach occasion within a relatively narrow time-window, to ensure, e.g.that a peak level is not inadvertantly recorded as a high response todosage.

[0020] Beyond all these very evident practical difficulties lies theoccurrence of undesirable side reactions already alluded to, observedemploying available oral dosage forms.

[0021] Several proposals to meet these various problems have beensuggested in the art, including both solid and liquid oral dosage forms.An overriding difficulty has however remained the inherent insolubilityof the cyclosporins, e.g. Ciclosporin, in aqueous media and henceprovision of a dosage from which can contain cyclosporins insufficiently high concentration to permit convenient use and yet meetthe required criteria in terms of bioavailability, e.g. enablingeffective resorption from the stomach or gut lumen and achievement ofconsistent and appropriately high blood/blood-serum levels.

[0022] As already noted, current commercial oral dosage forms forCiclosporin are disclosed and claimed, e.g. in U.S. Pat. No. 4,388,307.The early phase of this development is reflected in Swiss patentapplication no. 8634/78-8 which serves as a priority document to thispatent. This application is directed to galenic formulations comprisingCiclosporin as active ingredient together with a carrier mediumcomprising anyone or more of the following components:

[0023] i) sesame oil;

[0024] ii) a non-ionic tenside, e.g. Tween 80, Cremophore EL, 40 or 60or lecithins;

[0025] iii) a trans-esterified non-ionic triglyceride, e.g. Labrafil;

[0026] iv) mixtures of a lecithin (e.g. Epikuron), ingredients (iii) andethyloleate;

[0027] v) neutral oils, e.g. saturated C₈₋₁₂triglycerides such asMiglyol 812; and

[0028] vi) mono- and/or di-glycerides such as glycerol monooleate,glycerol monostearate and glycerol distearate.

[0029] In the text and examples: (i) is described for use alone, fororal or parenteral administration; (ii) are described for use incombination with ethanol for oral or parenteral administration and incombination with components (v) for parenteral application; (iii) aredescribed for use alone and in conjunction with a vegetable oil and,additionally, ethanol for oral or parenteral administration; (iv) isdescribed in terms of the defined combination with possible furtheradditives, for example conserving agents, for oral administration; (v)are described for use in combination with solvents such as ethanol,benzoic acid benzyl ester, 1,2-butyleneglycol-0.1-methyl ether andcomponents (iii) (Labrafil) as well as in combination with components(ii) as set forth above, in particular for parenteral administration;and (vi) are described for use alone or in combination with thickeningagents such as aerosil or cellulose for oral administration inencapsulated or pelleted form. No specific proposal is made for thecombination of components (vi) [mono-/di-glycerides] with any othercomponent (i) to (v), or vice versa.

[0030] In the patent application which matured as U.S. Pat. No.4,388,307, the focus of development set out in the above Swissapplication is concentrated on compositions comprising cyclosporins asactive ingredient, together with a carrier medium comprising one or moreof components (iii) [Labrafils etc.], (v) [neutral oils] and (vi)[mono-/di-glycerides, in particular stearic or oleic mono/di-glycerides,especially glycerol monooleate]. In relation to oral dosage forms, useof co-solvents, ethanol and vegetable oils such as olive oil and cornoil, is preferred. Components (v) are specifically indicated aspreferred in relation to parenteral, dosage forms. Components (vi) areproposed for use with lecithins, optionally together with components(iii) in orally administered aqueous or aqueous/ethanolic emulsions.

[0031] Belgian Patent no. 895 724, which relates primarily to the use of[dihydro-MeBmt]¹-[Val]²-Ciclosporin (or dihydro-cyclosporin D) in thetreatment of multiple sclerosis, also describes two oral formulationssuitable for the administration of this particular compound. Both ofthese are based on the commercial Ciclosporin (Sandimmun^(R))drink-solution, with adaptation to suit the particular cyclosporinactive ingredient. The first comprises 5-10%[Dihydro-MeBmt]¹-[Val]²-Ciclosporin, 10-12% ethanol, 30-40% Maisine, ca.4% Cremophore and 51-30% Labrafil (i.e. to 100%). This corresponds tothe composition of the Sandimmun^(R) drink-solution, but with thereplacement of the natural vegetable oil component with Maisine andintroduction of aminor pecentage of the tenside Cremophore. Maisine is atrans-esterification product of corn oil with glycerol, the more precisecomposition of which is described hereinafter. It comprises corn oilderived triglycerides and mono-/di-glycerides in the ratio ca. 1:8 p.p.w(tri-:mono-/di-glycerides). The ratio of cyclosporin: tenside in thedisclosed composition is ca. 1:0.4-0.8, and the ratio of cyclosporin:triglycerides: mono-/di-glycerides is ca. 1:0.4-0.9:2.6-7.1. No proposalis made for possible increase in the tenside component nor for any meansof avoiding the use of Labrafil or ethanol components as co-solvents.

[0032] The second disclosed composition comprises: 15-25%[Dihydro-MeBmt]¹-[Val]²-Ciclosporin, 2-5% ethanol, 40-60% Maisine and10-40% Imwitor 742, a coconut oil mono-glyceride product comprising >45%monoglycerides with additional di- and tri-glyceride components. Again,the use of ethanol is not avoided and no proposal is made forincorporation of any tenside component.

[0033] Australian patent application no. 87 335122 discloses the use oftensides belonging to the group comprising polyethoxylated castor oils,polyethoxylated hydrogenated castor oils and polyethoxylated fatty acidsderived from castor oil or hydrogenated castor oil, such as Cremophores,Myrj, and Nikkol HCO-60 as solubilizers for the incorporation ofdifficultly soluble pharmaceutical agents into controlled releasesystems, such as hydrophilic gel systems. Difficultly solublepharmaceuticals recited include Ciclosporine, though no example of theapplication of the system to cyclosporins is given. Nor is there anyteaching for the use of the recited solubilizers/tensides in conjunctionwith simple fatty acid mono-, di- or tri-glycerides.

[0034] In accordance with the present invention, it has now surprisinglybeen found that pharmaceutical compositions comprising cyclosporins, inparticular Ciclosporin, as active ingredient, which meet orsubstantially reduce difficulties in dosaging and patient acceptabilityhitherto encountered in the art, e.g. as discussed above, can beachieved by the use of carrier systems comprising fatty acidtri-glycerides and mono-/di-glycerides, suitably in combination aconjunction with a hydrophilic tenside. In particular, it has been foundthat, employing the defined carrier systems, it is possible to obtainoil-based compositions, which are not aqueous emulsions, and which donot require the presence of additional solvents, co-solvents orsolubilizers, for example ethanol or Labrafils or the like, and whichexhibit high stability as well as improved bioavailabilitycharacteristics as compared with known cyclosporin/fatty acidtriglyceride/solvent/co-solvent systems, for example, the knownSandimmun^(R) drink-solution. In a specific aspect the present inventionprovides for oil-based pharmaceutical compositions, in particularoil-based pharmaceutical compositions other than aqueous emulsions,which are free or substantially free of ethanol.

[0035] In particular, it has been found that compositions in accordancewith the present invention enable effective cyclosporin dosaging withconcomitant enhancement of resorption/bioavailability levels, and/orreduced variability in resorption/bioavailability levels, achieved bothfor individual patients receiving cyclosporin therapy as well as betweenindividuals. In particular it has surprisingly been found that thecompositions of the invention enable resorption of cyclosporins in amanner that is independent, or of substantially reduced dependency, uponthe relative availability of natural surfactant materials, e.g. bileacids or salts, in the gastro-intestinal tract of the subject treated.By application of the teachings of the present invention, cyclosporindosage forms are obtained providing reduced variability in achievedcyclosporin blood/blood serum levels between dosages as well as betweenindividuals. The invention thus enables reduction of cyclosporin dosagelevels required to achieve effective therapy. In addition, it permitscloser standardisation as well as optimisation of on-going daily dosagerequirements for individual subjects receiving cyclosporin therapy aswell as for groups of patients undergoing equivalent therapy.

[0036] By closer standardisation of individual patient dosaging rate andblood/blood-serum level response, as well as dosaging and response para-for patient groups, monitoring requirements may be reduced, thussubstantially reducing the cost of therapy.

[0037] By reduction of required cyclosporin dosaging/standardisation ofachieved bio-availability characteristics, the present invention alsoprovides a means which may permit reduction in the occurrence ofundesirable side-effects, in particular nephrotoxic reaction, inpatients undergoing cyclosporin therapy.

[0038] In addition, the compositions of the invention exhibit improvedstability on storage as compared with compositions based on the use ofethanol or equivalent alkanols and are, in particular, better adapted,e.g. for presentation in capsule, e.g. hard or soft gelatin capsule,form. Compositions in accordance with the findings of the presentinvention which are free or substantially free of ethanol have theparticular advantage of eliminating or substantially reducing packagingdifficulties, for example as hereinbefore discussed, e.g. in relation tothe packaging of soft gelatin encapsulated forms.

[0039] In accordance with the present invention there is provided, inits broadest aspect:

[0040] A. A pharmaceutical composition comprising:

[0041] a) a cyclosporin as active ingredient in a carrier mediumcomprising

[0042] b) a fatty acid triglyceride and

[0043] c) a glycerol fatty acid partial ester or propylene glycol (e.g.1,2-propylene glycol) or sorbitol complete or partial ester.

[0044] The term “pharmaceutical composition” as used throughout thepresent specification and accompanying claims is to be understood asdefining compositions of which the individual components or ingredientsare themselves pharmaceutically acceptable, e.g. where oraladministration is foreseen, acceptable for oral use or, where topicaladministration is foreseen, topically acceptable.

[0045] Component (a) in the compositions of the invention may be anytherapeutically applicable cyclosporin, e.g. as hereinbefore indicatedthe preferred component (a) in the compositions of the invention isCiclosporin. A further preferred component (a) in the compositions ofthe invention is [Nva]2-Ciclosporin, also known as cyclosporin G.

[0046] Components (b) and (c) in the compositions of the invention maycomprise or consist or consist essentially of the individual components(b) and (c) of a single ingredient, e.g. single material or product.Suitable products of this type include, in particular,transesterification products of vegetable oils with glycerol, propyleneglycol (e.g. 1,2-propylene glycol) or sorbitol.

[0047] Accordingly, in one particular series of embodiments the presentinvention provides:

[0048] B¹ A pharmaceutical composition comprising:

[0049] a) a cyclosporin as active ingredient in a carrier mediumcomprising

[0050] b+c) a transesterification product of a vegetable oil withglycerol, propylene glycol or sorbitol;

[0051] B² A pharmaceutical composition comprising:

[0052] a) cyclosporin as active ingredient in a carrier mediumcomprising

[0053] b+c) a transesterification product of a vegetable oil withglycerol or sorbitol; and

[0054] B³ A pharmaceutical composition comprising:

[0055] a) a cyclosporin as active ingredient in a carrier mediumcomprising

[0056] b+c) a transesterification product of a natural vegetable oil andglycerol or sorbitol.

[0057] Ingredients (b+c) for use in compositions of the invention asdefined under B¹ to B³ above include trans-esterification products ofany appropriate natural (e.g. non-hydrogenated) or hydrogenatedvegetable oil. Suitably they are, as specifically in the case ofdefinition B³, trans-esterification products of natural vegetable oils,for example, almond oil, ground-nut oil, olive oil, palm oil or,preferably, corn oil.

[0058] Such trans-esterification products [ingredients (b+c)] aregenerally obtained by heating of the vegetable oil, e.g. corn oil, withglycerol, propylene glycol or sorbitol [e.g. glycerol or sorbitol], athigh temperature under an inert atmosphere with continuous agitation,e.g. in a stainless steel reactor, to effect trans-esterification, e.g.glycerolysis, glycolysis or sorbitolysis. Ingredients (b+c) thuscomprise mixtures of mono-, di- and tri-glycerides (i.e. glycerol mono-,di- and tri-esters) with (generally minor amounts) of free glycerol.

[0059] Where ingredients (b+c) for use in the invention are obtained bytrans-esterification of a vegetable oil with sorbitol they will alsocontain free sorbitol as well as sorbitol mono-, di-, tri- andtetra-esters.

[0060] Where ingredients (b+c) for use in the invention are obtained bytrans-esterification of a vegetable oil with propylene glycol they willalso contain free propylene glycol (e.g. 1,2-propylene glycol) as wellas propylene glycol mono- and di-esters.

[0061] In general free sorbitol/free propylene glycol will be present inrelatively minor amounts, the recited mono-, di-, as well as tri- andtetra-esters when sorbitol is employed, in relatively substantialamounts.

[0062] The amount of triglyceride present in ingredients (b+c) for usein the invention will preferably be substantial, e.g. in excess of 5%,suitably from 7.5 to 12% by weight based on the total weight of theindividual components (b) and (c) in said ingredient.

[0063] The amount of free glycerol plus any free propylene glycol orsorbitol present in ingredients (b+c) for use in the invention ispreferably less than 10%, more preferably less than 5%, most preferably1 to 2% or less based on the total weight of said ingredient. The amountof mono-glyceride present in ingredients (b+c) for use in the inventionis preferably ca. 25 to 50%, more preferably ca. 30 to 45%, by weightbased on the total weight of said ingredient.

[0064] When (b+c) is a trans-esterification product of a vegetable oil,e.g. corn oil, and glycerol, the amount of free glycerol present in saidproduct is preferably less than 10%, more preferably less than 5%, mostpreferably less than ca. 4% by weight. The amount of mono-glyceridepresent is preferably about 30 or 35 to 50% by weight, more preferablyabout 35 or 40 to 45% by weight. The amount of di-glyceride present ispreferably less than about 60%, suitably less than 40%, by weight. Theamount of tri-glyceride present is preferably up to about 10% by weight,e.g. ca. 7.5 to 12 or 14% by weight (all percentages being based on thetotal weight of said product). The ratio of the components (b):(c) inthe defined trans-esterification products is thus suitably of the orderof ca. 1:8 to ca. 1:9 p.p.w.

[0065] When (b+c) is a trans-esterification product of a vegetable oil,e.g. corn oil, and sorbitol, the amount of free glycerol plus freesorbitol present in said product is preferably less than 5% by weight,more preferably ca. 1 to 2% by weight. The amount of mono-glyceridepresent is preferably ca. 30 to 40% by weight, more preferably ca. 35%by weight (all percentages being based on the total weight of saidproduct).

[0066] Particularly suitable trans-esterification products [ingredients(b+c)] for use in accordance with the present invention aretrans-esterification products of corn oil and glycerol, for example ascommercially available under the trade name Maisine. Such products arecomprised predominantly of linoleic and oleic acid mono-, di- andtri-glycerides together with minor amounts of palmitic and stearic acidmono-, di- and tri-glycerides (corn oil itself being comprised of ca.56% by weight linoleic acid, 30% oleic acid, ca. 10% palmitic and ca. 3%stearic acid constituents). Physical characteristics for Maisine[available from the company Etablissements Gattefossé, of 36, Chemin deGenas, P.O.Box 603, 69804 Saint-Priest, Cedex (France)] are: approximatecomposition free glycerol 10% max. (typically 3.9-4.9% or, in morerecent batches, ca. 0.2%) monoglycerides ca. 40% (typically 41-44.1% or,in more recent batches, ca. 38%) diglycerides ca. 40% (or, in morerecent batches, ca. 46%) triglycerides ca. 10% (or, in more recentbatches, ca. 12%) free oleic acid content ca. 1%

[0067] Further physical characteristics for Maisine are: acid value=max.ca. 2, iodine no.=ca. 85-105, saponification no.=ca. 150-175, mineralacid content=0.

[0068] The fatty acid content for Maisine is typically: palmiticacid—ca. 11%; stearic acid—ca. 2.5%; oleic acid—ca. 29%; linoleicacid—ca. 56%; others—ca. 1.5%.

[0069] Further trans-esterification products [ingredients (b+c)]suitable for use in accordance with the present invention aretrans-esterification products of corn oil and sorbitol, for example ascommercially available under the trade name Sorbito Glycerides from thecompany Etablissements Gattefossé, for example Sorbito Glycerides WL713, which has the following approximate composition:

[0070] Product: trans-esterification product of ca. 2 Mol corn oil andca. 1 Mol sorbitol: Approximate composition - free glycerol {closeoversize brace} ca. 1 to 2% free sorbitol monoglycerides ca. 35% plus:di- and tri-glycerides and sorbitol mono-, di-, tri- and tetra-esters.

[0071] Color (Echelle Garner)=<8. Highly soluble in ethanol andchloroform/slightly soluble in ethyl-ether/insoluble in H₂O. Acidno.=<1; saponification no.=ca. 160-185; iodine no.=ca. 110-140.

[0072] The carrier medium of compositions in accordance with B¹ to B³above may comprise (b+c) alone or together with one or more additionalexcipients, additives or other ingredients as known in the art, forexample diluents, solvents, stabilizing agents, tensides, sweeteningagents, preserving agents and/or flavouring agents.

[0073] Where ingredient (b+c) is semi-solid or of high viscosity e.g. asin the case of Maisine, the addition of a diluent or solvent to reduceviscosity will be especially advantageous, in particular to improvehandlability of the composition, for example to facilitate filling intocontainers, particularly where these are of small diameter as in thecase of ampoules, capsules and the like. Accordingly in a furtherembodiment the present invention also provides:

[0074] B⁴ A pharmaceutical composition as defined under any one of B¹ toB³ above additionally comprising:

[0075] d) a solvent or diluent miscible with (b+c) and reducing, orcapable of reducing, the viscosity of (b+c).

[0076] When present, component (d) suitably comprises atrans-esterification product of a natural vegetable oil triglyceride anda polyalkylene polyol. Such trans-esterification products are known fromthe art and may be obtained e.g. in accordance with the generalprocedures described in U.S. Pat. No. 3,288,824. They includetransesterification products of various natural (e.g. non-hydrogenated)vegetable oils for example, maize oil, kernel oil, almond oil, groundnut oil, olive oil and palm oil and mixtures thereof with polyethyleneglycols, in particular polyethylene glycols having an average molecularweight of from 200 to 800. Preferred components (d) aretrans-esterification products obtained from maize oil. Further preferredas (d) are products obtained by trans-esterification product of theclass defined are commercially available from Etablissement Gattefossé,Boulogne sur Seine, France under the trade name Labrafil [see Fiedler,loc. cit., page 539]. A preferred component (d) is the product LabrafilM 2125 CS, a plyoxyethylated, maize oil having an acid no.=ca. 2, asaponification no.=ca. 155-175 and an iodine no.=ca. 90-100.

[0077] Use of Labrafil as component (d) is especially indicated wherethe compositions of the invention are to be filled into ampoules or thelike for use as the base for a “drink solution” e.g. as hereinafterdescribed.

[0078] Further, especially advantageous components (d) are (additional)components (c) as defined under A above, in particular mono- anddi-glycerides, e.g. comprising an esterification product of caprylic andcapric acid with glycerol. Use of such components (c) as (d) providescompositions in accordance with the invention conforming with theinvention as hereinafter defined under C.

[0079] Examples of suitable components (c) for use as (d) include any ofthose described under (c.1) to (c.6) below. Especially preferredcomponents (c) for use as (d) comprise products obtained byesterification of from about 50 to 75, e.g. about 60, parts by weight ofcapric acid with glycerol, and comprising, or consisting mainly oressentially of caprylic/capric acid mono- and di-glycerides. Especiallypreferred products of this class are those available under the tradename Imwitor as described under (c.1) below, in particular the productImwitor 742.

[0080] A further possible, though less preferred, component (d) isethanol, e.g. absolute ethanol.

[0081] In addition it has also been found that the bio-availability ofthe compositions in accordance with B¹ to B³ above may be furtherincreased if they additionally comprise an emulsifying agent.Accordingly, in yet a further embodiment, the present inventionadditionally provides:

[0082] Bs A pharmaceutical composition as defined under any one of B¹ toB⁴ above additionally comprising:

[0083] e) an emulsifying agent.

[0084] Components (e) may or may not be directly miscible (e.g. capableof forming a solution, suspension or the like) with other componentspresent in the compositions defined, e.g. components (a) and (b+c).Where components (e) are non-miscible, the compositions of the inventionwill be bi-phasic, i.e. comprise at least a double-system e.g. withcomponents (a) and (b+c) and, optionally, (d) comprised in a first layeror phase of the composition and component (e) comprised in a second,separate layer or phase above or below the said first layer or phase(depending on the relative specific gravity of the two layers orphases). Such bi-phasic compositions are also to be understood as beingwithin the purview of the present invention. Where the compositions ofthe invention are bi-phasic, separate phases may be commingled prior toadministration, e.g. by shaking, stirring or other agitation, or may becontained together within a single unit dosage form, e.g. capsule or thelike, so as to permit concommitant administration and release within thegastro-intestinal tract. Component (e), when present, preferablycomprises a tenside having a hydrophilic-lipophilic balance (HLB) of atleast 10. Examples of suitable components (e) include any of thosedescribed under (e′.1) to (e′.8) below, in particular under (e′.1), mostespecially those known and commercially available under the trade nameCremophore, for example Cremophore RH40.

[0085] In the compositions of the invention in accordance with B¹ to B⁵above, (a) is suitably present in an amount of from about 2.0 to about20%, preferably from about 5 to 15%, most preferably about 10×by weight,based on the total weight of the composition. Accordingly, when (b+c) ispresent alone, this will generally be present in an amount of from about80 to about 98%, preferably from about 75 to about 95%, most preferablyabout 90% based on the total weight of the composition.

[0086] When (d) is present and is a trans-esterification product of anatural vegetable oil triglyceride and a polyalkylene plyol (for examplea Labrafil), (d) is suitably present in an amount of up to about 50%,preferably from about 20 to about 40%, most preferably about 30%, basedon the total weight of the composition.

[0087] When (d) is present and is an esterification product of caprylicand caproic acid with glycerol (for example an Imwitor), (d) is suitablypresent in an amount of up to 40%, preferably in an amount of from about2 to about 40%, most preferably in an amount of from about 2 to about20% based on the total weight of the composition.

[0088] When (d) is present and is ethanol, (d) is suitably present in anamount of up to about 10%, preferably in an amount of about 2-5% basedon the total weight of the composition.

[0089] When present, (e) is suitably present in an amount of up to 10%,preferably about 5% (e.g. ca. 6%), based on the total weight of thecomposition.

[0090] When present, components (d) and/or (e) will generally beintroduced in partial replacement of component/ingredient (b+c). Thuswhere the compositions of the invention comprise (a)+(b+c)+(e) [but not(d)] and (e) is present in an amount of 6% by weight based on the totalweight of the composition, (b+c) will generally be present in an amountof from about 74 to about 92%, preferably from about 69 to about 89%most preferably about 84% based on the total weight of the composition.

[0091] For the purposes of oral administration, the compositions of theinvention in accordance with B¹ to B⁵ above will preferably be put up inunit dosage form. In so far as the compositions are liquid this may bedone by filling into a solid pharmaceutical unit dosage container suchas capsule, e.g. a hard or soft gelatin capsule, for direct oraladministration or a phial or ampoule, e.g. for subsequent admixture witha drink-mixture, e.g. chocolate drink, prior to administration ascurrently practiced for the known cyclosporin “drink solution”. Wherethe compositions of the invention are bi-phasic as hereinbeforedescribed, the components may be homogenised to produce a uniformmixture prior to filling into the chosen dosage form, thus facilitatingthe filling procedure. Component (e) may then separate out from othercomponents present to form a separate phase or layer, e.g. after closureof the unit dosage form. Most preferably the compositions of theinvention are put up in soft gelatin capsule form.

[0092] In general: where unit dosage forms, e.g. of the type describedabove, are desired, components (a) and (b+c) are suitably present in thecompositions of the invention in a ratio of from about 1:4 to about1:50, preferably from about 1:5 to about 1:20, most preferably about 1:9p.p.w. [(a):(b+c)].

[0093] When a component (d) is present and this is thetrans-esterification product of a natural vegetable oil triglyceride anda polyalkylene polyol, components (d) and (b+c) are suitably present ina ratio of from about 1:1.25 to about 1:3.5, most preferably about 1:2p.p.w. [(d):(b+c)]. When a component (d) is present and is thetrans-esterification product of a natural vegetable oil triglyceride anda polyalkylene polyol, components (a), (b+c) and (d) are suitablypresent in a ratio of from about 1:9:0.1 to about 1:3.5:5.5, preferablyfrom about 1:7:2 to about 1:5:4, most preferably about 1:6:3 p.p.w.[(a):(b+c):(d)].

[0094] When a component (d) is present and this is a component (e) ashereinafter described, especially an esterification product of caprylicand caproic acid with glycerol, components (d) and (b+c) are suitablypresent in a ratio of from 1:50 to about 1:1, preferably from about 1:45to about 1:3.5 p.p.w. [(c):(b+c)]. When a component (d) is present andthis is an esterification product of caprylic and caproic acid withglycerol, components (a), (b+c) and (d) are suitably present in a ratioof from about 1:9:0.2 to about 1:5:4, preferably from about 1:8.8:0.2 toabout 1:7:2 p.p.w. [(a):(b+c):(d)].

[0095] When component (d) is present and is ethanol, components (d) and(b+c) are suitably present in a ratio of from about. 1:8 to about 1:90preferably from about 1:20 to about 1:45 p.p.w. [(d):(b+c)].

[0096] When a component (e) is present, components (a) and (e) aresuitably present in a ratio of from about 1:0.1 to about 1:5, preferablyfrom about 1:0.3 to about 1:1, most preferably about 1:0.5 p.p.w.[(a):(e)]. When a component (d) is present, components (a), (b) and (d)are suitably present in a ratio of from about.1:9:0.1 to about 1:8:1,preferably about 1:8.5:0.5 p.p.w. [(a):(b+c):(d)].

[0097] When components (d) and (e) are both present, and (d) is thetrans-esterification product of a natural vegetable oil triglyceride anda polyalkylene polyol, components (a), (b+c), (d) and (e) are suitablypresent in a ratio of from about 1:9:0.1:0.1 to about 1:3:5:1,preferably from about 1:6.5:2:0.5 to about 1:4.5:4:0.5, most preferablyabout 1:5.5:3:0.5 p.p.w. [(a):(b+c):(d):(e)].

[0098] In an alternative and specific embodiment, compositions of theinvention in accordance with B¹ to B⁵ above may be put up in unit dosagefrom by compounding or admixture with an appropriate pharmaceuticallyacceptable base material such that the obtained product or admixture iscapable of being formed into a solid unit dosage. In so far as thecompositions of the invention may themselves be solid or semi-solid,e.g. when (b+c) comprises Maizine or the like, particularly when (d) isabsent, such products and admixtures are readily achievable. Suitablebase materials include any of those known and commonly employed in theart and providing products and admixtures with the compositions of theinvention capable of being formed, e.g. moulded, pressed, cast orotherwise shaped, into unit dosage form.

[0099] For the preparation of unit dosage forms in this particularmanner, the compositions of the invention preferably comprise components(a) and (b+c) and, optionally (e), but not (d).

[0100] In contradistinction to compositions to be contained in anampoule or the like, it is further preferred that compositions accordingto the invention and processed in this manner comprise components (a)and (b+c) in a ratio of from about 1:1 to about 1:10, preferably fromabout 1:1 to about 1:5, most preferably about 1:2.5 p.p.w. [(a):(b+c)]

[0101] Preferred base materials for use in accordance with thisparticular modification of the present invention comprise in particularnatural fats, especially vegetable fats, for example cacao fat or cacaobutter and conventional chocolate bases, e.g. couverture chocolate andmixtures thereof. Where a natural fat is employed the ratio of (a) tofat is preferably from about 1:0.5 to about 1:2, more preferably fromabout 1:1 to about 1:1.5, most preferably about 1:1.25 p.p.w. [(a):fat].Where a chocolate base is employed the ratio of (a) to chocolate ispreferably from about 1:10 to about 1:50, more preferably from about1:10 to 1:30 and most preferably about 1:20 p.p.w. [(a):chocolate]. Bycompounding or admixture of a composition in accordance with theinvention with a fat and chocolate, e.g. in the above describedproportion, a product may be obtained in the form of a substantiallyhomogenous mass which can be put up in unit dosage form, e.g. by pouringas a warm melt into an appropriate mould, e.g. as described in thefollowing example 5, to provide a cyclosporin sweet meat, bon-bon orcandy as unit dosage form.

[0102] Alternatively components (a) and (b+c) may be filled, optionallytogether with component (d), into a chocolate mantel, cover or capsule.

[0103] Unit dosage forms in accordance with B¹ to B⁵ above suitablycontain from about 25 to 500, more preferably about 50 to 300,especially 50, 100, 150 or 200 mg of component (a), e.g. of Ciclosporin,for administration e.g. 1× or from 2 to 3× daily.

[0104] Compositions in accordance with the present invention, e.g. inaccordance with A or any one of B¹ to B⁵ above, which comprise acomponent (e) as hereinbefore set forth, in particular comprising (e′) atenside having an HLB of at least 10, are of especial interest. Inparticular such compositions have been found to be surprisingly andunexpectedly veil adapted to meet difficulties in the art hithertoencountered in relation to cyclosporin dosaging, e.g. as hereinbeforeparticularly discussed.

[0105] Accordingly, in an especially preferred embodiment, the presentinvention further provides:

[0106] C. A pharmaceutical composition comprising:

[0107] a) a cyclosporin as active ingredient in a carrier mediumcomprising

[0108] b) a fatty acid triglyceride,

[0109] c) a glycerol fatty acid partial ester or propylene glycol (e.g.1,2-propylene glycol) or sorbitol complete or partial ester, and

[0110] e′) a tenside having a hydrophilic-lipophilic balance (HLB) of atleast 10.

[0111] In a series of specific embodiments the present invention alsoprovides:

[0112] A composition as defined under C above, which composition:

[0113] i) is free or substantially free of ethanol; or

[0114] ii) comprises Ciclosporin or [Nva]²-Ciclosporin as component (a);or

[0115] iii) comprises components (a) and (e′) in a ratio of 1: at least1 p.p.w.

[0116] Provisos (i) to (iii) above are not mutually exclusive.Compositions in accordance with C complying with said provisos and inwhich components (b) and (c) comprise, or consist or consist essentiallyof the individual components of an ingredient or component (b+c) asdefined under any one of B¹ to B³ above, e.g. in which components (b)and (c) consist or consist essentially of the individual components of atrans-esterification product of a vegetable oil with glycerol, are ofparticular interest.

[0117] Component (a) is suitably present in the compositions as definedunder C above in an amount of from ca. 2-20%, more preferably ca. 5-15%based on the total weight of components (a) to (c) and (e′) inclusive.The preferred component (a) is Ciclosporin. A further preferredcomponent (a) is [Nva]²-Ciclosporin, also known as cyclosporin G.

[0118] Examples of suitable components (e′) in the compositions asdefined under C. above are:

[0119] e′.1 Reaction products of a natural or hydrogenated castor oiland ethylene oxide. Such products may be obtained in known manner, e.g.by reaction of a natural or hydrogenated castor oil with ethylene oxide,e.g. in a molar ratio of from about 1:35 to about 1:60, with optionalremoval of the polyethyleneglycol component from the product, e.g. inaccordance with the methods disclosed in German Auslegeschriften1,182,388 and 1,518,819. Especially suitable are the various liquidtensides available under the trade name Cremophor. Particularly suitableare the products Cremophor RH 40 having a saponification number of ca.50-60, an acid number <1, an iodine number <1, a water content(Fischer)<2%, an n_(D) ⁶⁰ of ca. 1,453-1,457 and an HLB of ca. 14-16;Cremophor RH 60 having a saponification number of ca. 40-50, an acidnumber <1, an iodine number <1, a water content (Fischer) 4.5-5.5%, andan n_(D) ²⁵ of ca. 1.453-1.457 and an HLB of ca. 15-17; and Cremophor ELhaving a molecular weight (by steam osmometry) of ca. 1630, asaponification number of ca. 65-70, an acid number of ca. 2, an iodinenumber of ca. 28-32 and an n_(D) ²⁵ of ca. 1.471. Also suitable for usein this category are the various tensides available under the trade nameNikkol, e.g. Nikkol HCO-40 and HCO-60. The said product Nikkol HCO-60 isa reaction product of hydrogenated castor oil and ethylene oxideexhibiting the following characteristics: acid value ca. 0.3;saponification number of ca. 47.4; hydroxy value of ca. 42.5; pH (5%) ofca. 4.6; color APHA=ca. 40; m.p.=ca. 36.0° C.; freezing point=ca. 32.4°C.; H₂O content (%, KF)=0.03.

[0120] e′.2 Polyoxyethylene-sorbitan-fatty acid esters, e.g. mono- andtri-lauryl, palmityl, stearyl and oleyl esters, e.g. of the type knownand commercially available under the trade name Tween (c.f. Fiedler,“Lexikon der Hilfstoffe”, 2nd revised and expanded edition (1981),Vol.2, p.p. 972-975) including the products Tween 20[polyoxyethylene(20)sorbitanmonolaurate], 40[polyoxyethylene(20)sorbitanmonopalmitate], 60[polyoxyethylene(20)sorbitanmonostearate], 65[polyoxyethylene(20)sorbitantristearate], 85[polyoxyethylene(20)sorbitantrioleate], 21[polyoxyethylene(4)sorbitanmonolaurate], 81[polyoxyethylene(5)sorbitanmonooleate].

[0121] Especially preferred products of this class for use in thecompositions of the invention are the above products Tween 40 and Tween80.

[0122] e′.3 Polyoxyethylene fatty acid esters, for examplepolyoxy-ethylene stearic acid esters of the type known and commerciallyavailable under the trade name Myrj (c.f. Fiedler, loc. cit., 1, p.228);an especially preferred product of this class for use in thecompositions of the invention is the product Myrj 52 having a D²⁵=ca.1.1., m.p.=ca. 40-44° C., an HLB value=ca. 16.9., an acid value=ca. 0-1and a saponification no.=ca. 25-35.

[0123] e′.4 Polyoxyethylene-polyoxypropylene co-polymers and blockco-polymers, e.g. of the type known and commercially available under thetrade names Pluronic, Emkalyx and Poloxamer (c.f. Fiedler, loc. cit., 2,p.p. 720-723). An especially preferred product of this class for use inthe compositions of the invention is the product Pluronic F68, having anm.p.=ca. 52° C. and a molecular weight of ca. 6800-8975. A furtherpreferred product of this class for use in the compositions of theinvention is the product Poloxamer 188.

[0124] e′.5 Diotylsuccinate or di-[2-ethylhexyl]-succinate (c.f.Fiedler, loc. cit., 1, p.p. 307).

[0125] e′.6 Phospholipids, in particular lecithins (c.f. Fiedler, loc.cit., 2, p.p. 559-560). Lecithins suitable for use in the compositionsof the invention include, in particular, soya bean lecithins.

[0126] e′.7 Propylene glycol mono- and di-fatty acid esters such aspropylene glycol dicaprylate (also known and commercially availableunder the trade name Miglyol 840), propylene glycol dilaurate, propyleneglycol hydroxystearate, propylene glycol isostearate, propylene glycollaurate, propylene glycol ricinoleate, propylene glycol stearate and soforth (c.f. Fiedler, loc. cit., 2, p.p. 760 et seq.).

[0127] e′.8 Sodium lauryl sulfate.

[0128] The ratio of components (a):(e′) in the compositions inaccordance with C. above is suitably of the order of 1:1 to 25 p.p.w.,more preferably 1:1.25 to 20 p.p.w., yet more preferably 1:1.5 to 8 or10 p.p.w, e.g. ca. 1:2 to 5 p.p.w. Most preferably the ratio ofcomponents (a):(e′) is 1: at least 2 p.p.w. Component (a) is thussuitably present in the compositions of the invention in an amount e.g.of from ca. 20-50%, more preferably 25-40×, by weight based on the totalweight of components (a) and (e′).

[0129] Components (b) and (c) in compositions in accordance with C.above may comprise or consist or consist essentially of the individualcomponents (b) and (c) of a single ingredient, e.g. single material orproduct. Examples of ingredients comprising both components (a) and (b)suitable for use in the present invention include for example knownmixed fatty acid tri-glyceride and fatty acid mono-/di-glycerideproducts. Suitable products of this type include, in particular,transesterification products of vegetable oils with glycerol, propyleneglycol (e.g. 1,2-propylene glycol) or sorbitol e.g. as hereinbeforedescribed in relation to definitions B¹ to B³ above.

[0130] Suitable components of this type thus include any ingredient(b+c) as hereinbefore described, in particular products of the typeMaisine and Sorbito Glycerides.

[0131] In the case of compositions in accordance with C. above of whichthe components (b) and (c) consist or consist essentially of theindividual components (b) and (c) of a single ingredient, e.g. of whichthe components (b) and (c) are comprised entirely or substantiallyentirely of trans-esterification products as hereinbefore describedabove, the ratio of (a):(b+c) is suitably of the order of 1:0.75-35,preferably 1:1-25 p.p.w., more preferably the ratio is of the order of1:3-10, especially ca. 1:6 p.p.w. Where only ingredients comprising both(b) and (c) are employed, (b+c) are thus suitably present in thecompositions of the invention in an amount of from ca. 15-70%, morepreferably ca. 20-50% by weight, based on the total weight of components(a) to (c) and (e′) inclusive.

[0132] To enable combination of components (b) and (c) in thecompositions of the invention, e.g. as defined under C. above, inpreferred proportion as hereinafter described, component (b) in thecompositions of the invention will however preferably comprise at leastone ingredient definable as a fatty acid triglyceride as such, e.g.material or product, which is, or which consists or consists essentiallyof components (b) as hereinbefore defined (i.e. fatty acidtriglycerides), e.g. which comprises at least 75%, preferably at least90%, more preferably at least 95% by weight of components (b). Component(c) in the compositions of the invention will also preferably compriseat least one ingredient which is definable as a glycerol fatty acidpartial ester or propylene glycol or sorbitol complete or partial esteras such, e.g. which is or which consists or consists essentially ofcomponents (c) as hereinbefore defined, e.g. which comprises at least75%, preferably at least 90%, more preferably at least 95% by weight ofsaid components (c).

[0133] More preferably components (b) and (c) in the compositions of theinvention, e.g. as defined under c. above, will comprise separateingredients combinable in selected proportion [(b):(c)] as hereinafterdescribed. With respect to the components (b) and (c), the compositionsof the invention will thus most preferably comprise a bi-partitecombination of ingredients complying with definition (b) and ofingredients complying with definition (c), e.g. a combination of a firstingredient or ingredients consisting or consisting essentially ofcomponents (b) and of a second ingredient or ingredients consisting orconsisting essentially of components (c).

[0134] Suitable components (b) include both saturated (includinghydrogenated) and unsaturated fatty acid tri-glycerides, in particularanimal or vegetable oils. The fatty acid constituents of components (b)suitably include, saturated or mono-, di- or poly-unsaturated acidshaving e.g. chain lengths of from 6 to 22 carbon atoms. Especiallysuitable for use in accordance with the invention are fatty acidtriglycerides having a high content of unsaturated fatty acidconstituents in particular mono-, di- and poly-unsaturated fatty acidshaving at least 16 carbon atoms, preferably 18 carbon atoms or more, inparticular having a high oleic, linoleic or linolenic fatty acidconstituent content. Of particular interest are fatty acid triglycerideshaving a linoleic and/or linolenic acid constituent content of at least45%, preferably at least 60% and up to 65 or 80%, e.g. wheresuper-refined oils are used.

[0135] A first group of fatty acid triglycerides suitable for use inaccordance with the invention includes saturated C₆₋₁₂ fatty acidvegetable oil triglycerides, e.g. caprylic-capric acid triglycerides.Examples of ingredients suitable as components (b) thus includefractionated vegetable oils, e.g. fractionated coconut oils such as areknown and commercially available under the trade name Miglyol (c.f.Fiedler, loc. cit., 2, 615 and 616), including Miglyol 810, afractionated coconut oil, caprylic-capric acid triglyceride having amolecular weight of ca. 520 and a fatty acid constitution ═C₆ max. ca.2%, C₈ ca. 65-75%, C₁₀ ca. 25-35%, C₁₂ max. ca. 2%. Miglyol 810 has thefollowing further physical characteristics: α_(D) ²⁰=1.4490-1.4510, acidno.=max. 0.1, saponification no. =ca. 340-360, iodine value=max. 1.Especially preferred is Miglyol 812, a fractionated coconut oil,caprylic-capric acid triglyceride having a molecular weight of ca. 520,and a fatty acid constitution=C₆,max. ca. 3%, C₈ ca. 50-65%, C₁₀ ca.35-40%, C₁₂ max. ca. 5%. Miglyol 812 has the following further physicalcharacteristics: α_(D) ²⁰=1.4480-1.4500, saponification no.=ca. 330-345,iodine value=max. 1.

[0136] Further ingredients of similar class suitable for use ascomponents (b) include those known and commercially available under thetrade name Estasan, for example Estasan GT 8-60 and GT 8-65. Estasan GT8-60 is a vegetable oil fatty acid triglyceride in which the fatty acidcomponents are comprised chiefly of saturated C₈₋₁₀fatty acids, inparticular caprylic and capric acids. Fatty acid constitution=caproic(C₆) max. ca. 3%, caprylic (C₈) max. ca. 50-65%, capric (C₁₀) max. ca.35-45%, lauric (C₁₂) max. ca. 3%. Estasan GT 8-60 exhibits the followingadditional physical characteristics: saponification no.=ca. 325-345,iodine no.=max. ca. 1, acid value=max. ca. 0.1 α_(D) ²⁰=ca. 1.448-1.451.Estasan GT 8-65 is also a vegetable oil fatty acid triglyceride,comprised chiefly of saturated C₈₋₁₀fatty acids, in particular caprylicand capric acids. Fatty acid constitution=caproic max. ca. 1%, caprylicmin. ca. 65%, capric ca. 25-35%, lauric max. ca. 1%.

[0137] Yet further ingredients of this class are those known andcommercially available under the trade name Myritol, for example Myritol318 [c.f. Fiedler, loc. cit., 2, p.p. 635-636]. Myritol 318 is acaprylic/capric acid triglyceride having a saponification no. =ca.340-350, an iodine no. =ca. 0.5 and an n_(D) ²⁰=ca. 1.448-1.450.

[0138] Further ingredients suitable for use as components (b) include,e.g. vegetable oils such as corn oils, almond oils, kernel oils (forexample apricot kernel oils), avocado oils, babassu oils, higher fattyacid coconut oils, primrose oils, grapeseed oils, menhaden oils, oliveoils, orange roughy oils, peanut oils, safflower oils, sesame oils,soybean oils and wheat-germ oils as well as animal oils such as fishoils, e.g. fish liver oils, for example shark oils, and mink oils.Refined oils of any of the above types are of particular interest foruse in accordance with the present invention, in particular refinedplant oils, e.g. having the following approximateoleic/linoleic/linolenic acid constituent content: OLEIC LINOLEICLINOLENIC ACID ACID ACID EXAMPLE ca. 9% ca. 68% ca. 15% evening primroseca. 27% ca. 64% — grapeseed ca. 4% ca. 13% ca. 76% safflower ca. 5% ca.40% ca. 47% sesame ca. 25% ca. 54% ca. 6% soybean ca. 14% ca. 58% ca. 8%wheat-germ

[0139] Component (c) for use in compositions of the invention, e.g. asdefined under C. above, suitably comprises a glycerol fatty acid partialester, i.e. a fatty acid mono- or di-glyceride, or acetylated derivativethereof. Ingredients suitable for use as component (c) will preferablybe free or substantially free of any fatty acid tri-glyceride component,e.g. contain less than 25%, preferably less than 10%, more preferablyless than 5%, e.g. less than 1 or 2% fatty acid triglycerides.

[0140] Components (c) as aforesaid include both symmetric mono- anddi-glycerides (i.e. β-monoglycerides and α,α¹-diglycerides) as well asassymmetric mono- and di-glycerides (i.e. α-monoglycerides andα,β-diglycerides) and acetylated derivatives thereof. They also includeboth uniform glycerides (i.e. in which the fatty acid constituent iscomposed primarily of a single fatty acid) as well as mixed glycerides(i.e. in which the fatty acid constituent is composed of various fattyacids) and acetylated derivatives thereof.

[0141] The fatty acid constituent of components (c) may include bothsaturated and unsaturated fatty acids having a chain length of from 6 to22 carbon atoms. Preferably the fatty acid constituent willpredominantly comprise saturated or unsaturated fatty acids having achain length of from 8 to 18 carbon atoms, in particular 8, 10 or 14 to18, e.g. 16 or 18 carbon atoms. Especially suitable are mono- anddi-glycerides in which the fatty acid constituent is comprisedpredominantly of one or more members selected from the group consistingof caprylic, capric, linolenic, palmitic, stearic and oleic acids.

[0142] Particularly preferred for use as components (c) are ingredientscomprising mono- and di-glycerides, wherein the mono-/di-glyceridecontent is at least 50%, preferably at least 60%, more preferably atleast 75% by weight, and acetylated derivatives thereof. Examples ofappropriate ingredients for use as components (c) are:

[0143] c.1 Fatty acid mono- and di-glycerides, e.g. products obtained orobtainable by esterification of from about 50 to 75, e.g. about 60,parts by weight, and from about 50 to about 25, e.g. about 40, parts byweight of capric acid with glycerol, and comprising, or consistingmainly or essentially of caprylic/capric acid mono- and di-glycerides.Examples of such products include those known and commercially availableunder the trade name Imwitor (c.f. Fiedler, loc. cit., 1, p. 491), inparticular: caprylic and capric acid mono- and di-glycerides such asImwitor 742. Imwitor 742 is the esterification product of a mixtrue ofca. 60 p.p.w. caprylic acid and ca. 40 p.p.w. capric acid with glycerol.It comprises ca. 0.40 to 50% or more mono-glycerides. It is a yellowishcrystalline mass, liquid at ca. 26° C. It exhibits the following,additional characterising data—acid value=max. ca. 2%, iodine value=max.ca. 1.0, saponification no. =ca. 250-280, free glycerol content=max. ca.2%, unsaponifiables=0.3% max., peroxide no. =max 1; and stearic acidmono-glycerides such as Imvitor 191, which comprises at least 90%mono-glycerides as aforesaid and exhibits the following, additionalcharacterising data—m.p.=ca. 63-66° C., acid value=max. ca. 3,saponification no. =ca. 160-170, iodine value=max. ca. 3, free glycerolcontent=max. ca. 2%, and Imwitor 960K which comprises 30-40%monoglycerides as aforesaid and exhibits the following, additionalcharacterising data—m.p. rising from ca. 56 to ca. 60° C.,saponification no.=ca. 155-170, acid value=max. ca. 3, iodine value=max.ca. 3, free glycerol content=max. ca. 4%.

[0144] c.2 Fatty acid mono- and di-glycerides as commercially availableunder the trade name Cutina (c.f. Fiedler, loc. cit., 1, p.p. 263 and264): in particular palmitic and stearic acid mono- and di-glyceridessuch as Cutina MD-A, which comprises mono- and di-glycerides asaforesaid and exhibits the following characterising data—acid value=max.ca. 8, saponification no.=ca. 160-170; and stearic acid mono-glyceridessuch as Cutina GMS which comprises mono-glycerides as aforesaid andexhibits the following characterising data—m.p.=ca. 54-60° C., acidvalue=max. ca. 2, saponification no=ca. 162-173, iodine value=max. ca.2.

[0145] c.3 Fatty acid mono-glycerides as commercially available underthe trade name Myverol (c.f. Fiedler, loc. cit., 2, 637), in particularC₁₈ fatty acid, e.g. linolenic acid, mono-glycerides such as Myverol18-92, which comprises at least 90% mono-glycerides as aforesaid andexhibits the following additional characterising data: acid value=max.ca. 3.0, diglyceride content=max. ca. 5%, free glycerol content=max. ca.1.2%.

[0146] c.4 Fatty acid mono-glycerides as commercially available underthe trade name Myvaplex (c.f. Fiedler, loc. cit., 2, 637), in particularstearic acid mono-glycerides such as those of the Myvaplex 600 series,e.g. Myvaplex 600P which comprises ca. 94-90% mono-glycerides asaforesaid and exhibits the following additional characterisingdata—m.p.=ca. 73° C., density=ca. 0.92 g/cm³ at 80° C.

[0147] c.5 Fatty acid mono-glycerides as commercially available underthe trade name Estagel, for example Estagel G-18 which is comprisedprimarily of C₁₆₋₁₈ fatty acid mono-glycerides in particular palmiticand stearic acid mono-glycerides. The α-monoglyceride content of EstagelG-18 is min. ca. 40%. Further characterising data: acid value=max. ca.2, saponification no.=ca. 162-173, iodine no.=max. ca. 3, free glycerolcontent=max. ca. 6%.

[0148] c.6 Acetylated fatty acid mono- and di-glycerides such ascommercially available under the trade name Myvacet (c.f. Fiedler, loc.cit., 2, p.p. 636-637), in particular mono- and di-acetylated fatty acidmono-glycerides, for example mono- and di-acetylated stearic acidmono-glycerides such as: Myvacet 9-40 which has the followingcharacterising data—α_(D) ⁵⁰=ca. 1.4468-1.4476, m.p.=ca. 5° C., acidvalue=max. ca. 1.5, saponification no. =ca. 375-385; and Myvacet 9-45which has the following characterising data—α_(D) ⁵⁰=ca. 1.4465-1.4475,m.p.=ca. 8-12.4° C., acid value=ca. 1.5, saponification no.=ca. 375-385.

[0149] Further components (c) which are of particular utility, are mixedglycerol fatty acid partial esters and propylene glycol complete andpartial esters, e.g. products comprising fatty acid mono- anddi-glycerides and propylene glycol fatty acid mono- and di-esters.Examples of such components (c) include:

[0150] c.7 Fatty acid mono- and di-glycerides/propylene glycol fattyacid mono- and di-esters as commercially available under the trade nameAtmos [c.f. Fiedler, loc. cit., 1, p. 156], in particular Atmos 300 inwhich the fatty acid moieties are comprised principally of oleic acidresidues and Atmos 150 in which the fatty acid moieties are comprisedprincipally of stearic acid residues.

[0151] c.8 Fatty acid mono- and di-glycerides/propylene glycol fattyacid mono- and di-esters as commercially available under the trade nameArlacel [c.f. Fiedler, loc. cit., 1, p.p. 143-144] in particular Arlacel186 in which the fatty acid moieties are comprised principally of oleicacid residues.

[0152] Components (b) and (c) are preferably present in the compositionsof the invention, e.g. as defined under C. above, in a ratio of about1:0.02 to 3.0 p.p.w. More preferably the ratio of components (b):(c) isof the order of 1:0.1 to 2.5 p.p.w., most preferably 1:0.25-1.25 p.p.w.When components (b) and (c) in the compositions of the invention, e.g.compositions C, comprise separate ingredients, e.g. as described above,the said ingredients will thus suitably be employed in the same relativeratios. The amount of components (b) in the compositions of theinvention as defined under C. above is thus suitably of the order offrom 10-50%, preferably 20-40% by weight, based on the total weight ofcomponents (a) to (c) and (e′) inclusive, and the amount of components(c) in said compositions is suitably of the order of from 1-30%,preferably 10-25% by weight, based on the total weight of components (a)to (c) and (e′) inclusive.

[0153] The ratio of components (a):(b) plus (c) in the compositions ofthe invention, e.g. as defined under C, is suitably of the order of1:0.5 to 40 p.p.w. Preferably, the ratio of (a):(b) plus (c) is about1:1 to 35, more preferably about 1:1.5 to 30 p.p.w., most preferablyabout 1:2 to 6.

[0154] In accordance with the foregoing the present invention alsoprovides

[0155] D. A pharmaceutical composition as defined under C abovecomprising at least one ingredient which consists or consistsessentially of, a component or components as defined under (b) above;

[0156] E. A pharmaceutical composition as defined under C abovecomprising at least one ingredient which consists or consistsessentially of a component or components as defined under (c) above;

[0157] F. A pharmaceutical composition as defined under C above in whichcomponents (a) and (b) comprise separate ingredients.

[0158] The compositions of the invention, e.g. as defined under any of Cto F above, may include further components, for example thickeningagents, granulating agents, dispersing agents, flavouring and/orcolouring agents or anti-microbial agents etc . . . as required. Theymay also include polymeric thickening agents to permit processing into asolid or semi-solid mass suitable for tabletting or forming intogranules.

[0159] The compositions of the invention, in particular as defined underany of C to F above, will suitably include anti-oxidants to improveshelf-life, for example butyl-hydroxy-toluene (or BHT),butyl-hydroxy-anisole (or BHA), ascorbyl palmitate, ascorbic acid,citric acid or α-tocopherol-acetate.

[0160] In particular the compositions of the invention will suitablycomprise one or more stabilizers or buffering agents, e.g. to preventdegradation of component (a) during processing or on storage. Suchstabilizors may include acid stabilizers such as citric acid, aceticacid, tartaric acid or fumaric acid as well as basic stabilizers such aspotassium hydrogen phosphate, glycine, lysine, arginine ortris(hydroxymethyl)aminomethane.

[0161] Such stabilizors or buffer agents will appropriately be added inan amount sufficient to achieve or maintain a pH within the range offrom about 5 to 7, more preferably between 6 and 7.

[0162] When components (b) and (c) in the compositions of the inventionare comprised of a single ingredient which is the trans-esterificationproduct of a vegetable oil with glycerol, the compositions of theinvention will preferably be subject to proviso (i) as set forth underC. above, i.e. they will be free or substantially free of ethanol.Suitably they will be free or substantially free of any furthercomponent serving as a diluent or as a solvent medium for component (a),e.g. free of any such diluent or solvent other than a component (b), (c)or (b+c) as hereinbefore described.

[0163] While proviso (i) is applied above in a specific instance,compositions in accordance with the invention which are free orsubstantially free of ethanol are in general preferred. Compositions inaccordance with the invention which are free or substantially free ofany further component serving as a diluent or as solvent medium for (a),are also, in general, preferred. In a yet further series of embodimentsthe present invention thus also provides:

[0164] G. A pharmaceutical composition as defined under any one of (A)to (F) above which is free, or substantially free, of ethanol; and

[0165] H. A pharmaceutical composition as defined under any one of (A)to (F) above which is free or substantially free of any furthercomponent serving as a diluent or as solvent medium for component (a).

[0166] Compositions as aforesaid suitably comprise less than 2%, moresuitably from 0 to 0.5 or 1% by weight ethanol, based on the totalweight of the component ingredients. Compositions as aforesaid suitablycomprise less than 20%, more preferably less than 10%, e.g. from 0 to2.5 or 5.0% by weight further components serving as diluent or assolvent medium for component (a). Specific compositions in accordancewith the present invention are pharmaceutical compositions as definedunder any one of A. to H. above consisting, or consisting essentially,of components (b), (c) and (e)/(e′) as carrier medium for (a), i.e.exclusive of any thickening, granulating, dispersing, flavouring,colouring, stabilizing agents or the like excipients that may also bepresent, and which are present as additives to the carrier medium.

[0167] By components serving as diluents are in particular to beunderstood, components serving to reduce the viscosity/increase thefluidity of the compositions of the invention. By components serving assolvent medium for (a) are in particular to be understood co-solvents orother materials which enhance the solubility of components (a) in thecompositions of the invention. Examples of such components are, inparticular, solvent or diluent components having an HLB of less than 10,for example, trans-esterification products of natural vegetable oiltriglycerides and polyalkylene polyols such as known and commerciallyavailable under the trade name Labrafil and ethanol.

[0168] Compositions in accordance with the invention may be applied indosage form suitable for administration by any appropriate means, e.g.in the form of creams, gels or the like for topical or occularadministration, or in the form of granules, tablets, capsules,drink-solutions or the like for oral administration or in a formsuitable for intra-lesional application, e.g. in the treatment ofpsoriasis. Preferably however the compositions of the invention will beadministered orally. In a preferred embodiment the invention accordinglyprovides a composition as hereinbefore defined in a form appropriate oradapted for oral administration, in particular in oral unit dosage form.Especially suitable unit dosage forms for oral administration includeencapsulated forms, e.g. soft or hard gelatin encapsulated forms.

[0169] Oral unit dosage forms in accordance with the invention, inparticular in accordance with any of definitions C to F above, willsuitably comprise from 5 to 200 mg, more preferably from 20 to 100 mg,e.g. ca. 25, 50 or 100 mg component (a), e.g. for administration2-5×daily.

[0170] In addition to the foregoing the present invention also providesa process for the production of pharmaceutical compositions ashereinabove defined and described which process comprises intimatelyadmixing components (a), (b), (c) or (b+c) and, when present, (d) and/or(e)/(e′) thereof.

[0171] In a preferred aspect the present invention provides a process asaforesaid, which process comprises intimately admixing a component (a)with a first ingredient (b) which consists or consists essentially ofone or more fatty acid triglycerides and a second ingredient (c) whichcomprises a glycerol fatty acid partial ester or propylene glycol orsorbitol complete or partial ester, or with a first ingredient (b) whichcomprises a fatty acid triglyceride and a second ingredient (c) whichconsists or consists essentially of one or more glycerol fatty acidpartial esters and/or propylene glycol and/or sorbitol complete orpartial esters, and with (e′) a tenside having a hydrophilic-lipophilicbalance of at least 10.

[0172] In a more preferred aspect the present invention provides aprocess as aforesaid, which process comprises intimately admixing acomponent (a) with a first ingredient (b) which consists or consistsessentially of one or more fatty acid triglycerides, a second ingredient(c) which consists or consists essentially of one or more glycerol fattyacid partial esters and/or propylene glycol and/or sorbitol complete orpartial esters, and (e′) a tenside having a hydrophilic-lipophilicbalance of at least 10.

[0173] The following examples are illustrative of the manufacture ofcompositions in accordance with the present invention:

EXAMPLE 1

[0174] A composition is prepared by intimate admixture of the followingcomponents in the indicated relative amounts. COMPONENT AMOUNT a)Ciclosporin 100 mg (= ca. 10.5%) b + c) Maisine 550 mg (= ca. 57.8%) d)Labrafil M 2125 300 mg (= ca. 33.5%) TOTAL 950 mg

[0175] The components are thouroughly admixed in conventional manner andthe obtained mixture filled into standard soft gelatin capsulescontaining 950 mg composition per capsule.

EXAMPLE 2

[0176] Example 1 is repeated but using the following components in theindicated relative amounts: COMPONENT AMOUNT a) Ciclosporin 100 mg (=ca. 10.5%) b + c) Maisine 490 mg (= ca. 52%) d) Labrafil M 2125 300 mg(= ca. 31.5%) e′) Cremophore RH40 60 mg (= ca. 6.3%) TOTAL 950 mg

[0177] The composition is filled into soft gelatin capsules containing950 mg composition/capsule. Subsequent to sealing component (d)separates out from other components present.

EXAMPLE 3

[0178] Example 1 is repeated but using the following components in theindicated relative amounts: COMPONENT AMOUNT a) Ciclosporin 100 mg (=ca. 10.5%) b + c) Maisine 850 mg (= ca. 89.5%)

[0179] The composition is filled into soft gelatin capsules containing950 mg composition/capsule.

EXAMPLE 4

[0180] Example 1 is repeated but using the following components in theindicated relative percentages. COMPONENT % a)(Dihydro-MeBmt)¹-(Val)²-Ciclosporin 15-25% (also knovn asdihydrocyclosporin D) b + c) Maisine 40-60% c) Imwitor 742 10-40% d)Ethanol 2-5%

[0181] (Imwitor 742=a glycerine ester available from Dynamite Nobel AG,Troisdorf-Obelar, SN).

[0182] The quantitiy of a) required for a single dosage (ca. 100-200 mg)is dissolved in the remaining components using conventional techniquesto give a solution for filling into a soft gelatin capsule. QANTITYCOMPONENT (g) a) Ciclosporin + 4.0 7% excess 0.028 4.028 b + c) Maisine10.0 x) Cacao fat 5.0 y) Chocolate base 80.97 (couverture chocolate)Total 99.998

[0183] Components (x) and (y) are mixed thoroughly on a water bath at40° C. Component (a) is dissolved in component (b+c) under a nitrogenatmosphere and the obtained mixture added to the mixture of (x)+(y). Thewhole is mixed thoroughly on a water bath at 40° C. and then filled intomoulds in 2,500 mg portions, each portion containing 150 mg cyclosporinA. The moulds are stored overnight in a refrigerator and the obtainedunit dosage forms sealed in individual plastic sachets.

EXAMPLE 6

[0184] QUANTITY INGREDIENT (mg) a) Cyclosporin (e.g. Ciclosporin) 50.00b) Miglyol 812 100.00 c) Myverol 18-92 100.00 e′) Cremophore RH 40 50.00

EXAMPLE 7

[0185] Soft or hard gelatine capsules each comprising the followingindicated ingredients in the indicated amounts, are prepared analogouslyto Example 1: QUANTITY INGREDIENT (mg) 7a a) Cyclosporin (e.g.Ciclosporin) 50.00 b) Miglyol 812 100.00 c) Imwitor 742 100.00 e′)Cremophore RH 40 100.00 7b a) Cyclosporin (e.g. Ciclosporin) 50.00 b +c) Maisine 300.00 e′) Cremophore RH 40 100.00 7c a) Cyclosporin (e.g.Ciclosporin) 50.00 b) Soyabean oil 150.00 c) Myverol 18-92 50.00 e′)Emulgin R040* 250.00 7d a) Cyclosporin (e.g. Ciclosporin) 50.00 b)Sesame oils 150.00 c) Imwitor 900K 125.00 e′) Emulphor EL-719* 150.00 7ea) Cyclosporin (e.g. Ciclosporin) 50.00 b) Myritol 318 75.00 c) EstagelG-18 100.00 e′) Pluronic F68 175.00 7f a) Cyclosporin (e.g. Ciclosporin)50.00 b) Estasan GT 8-60 130.00 c) Arlacel 186 75.00 e′) Tween 80 125.007g a) Cyclosporin (e.g. Ciclosporin) 50.00 b) + c) Maisine 100.00 c)Myverol 18-92 200.00 e′) Cremophore RH40 100.00 7h a) Cyclosporin (e.g.Ciclosporin) 50.00 b) Miglyol 812 100.00 c) Myverol 18-92 200.00 e′)Cremophore RH40 100.00

[0186] The compositions obtained in accordance with examples 1 to 7 aresuitable for administration for the prevention of transplant rejectionor in the treatment of auto-immune disease, e.g. on administration offrom 1 to 5 unit dosages, e.g. capsules, daily. Equivalent compositionmay be prepared substituting any other Cyclosporin, e.g.[Nva]²-Ciclosporin, as component (a) in the same or equivalent amount.

[0187] Utility of compositions in accordance with the invention may beshown in animal or clinical trials, for example performed as follows:

[0188] Bioavailability Study for Compositions in Accordance with theInvention in the Dog

[0189] Study I

[0190] Test Dosage Forms

[0191] A. Unit dosages obtained in accordance with the above example 5,each unit dosage comprising 100 mg Ciclosporin.

[0192] B. Hard-gelatin capsules, each capsule containing 50 mgCiclosporin compounded with 50 mg ethanol, 150 mg Labrafil M. 1944 CSand 212.5 mg olive oil (=currently commercially available Ciclosporin“drink solution”).

[0193] Prepartions A and B are administered to male beagle dogs inrandomised, cross-over sequence. Both preparations are administereddirectly into the oesophagus and swallowed without chewing, andaministration is followed by washing out of the oesophagus with 10 mlwater delivered as a spray. Preparation A is administered in singledosages. Preparation B is administered in double dosage (=100 mgcyclosporin A).

[0194] 2 ml blood samples are taken prior to administration (control)and subsequent to administration at intervals of 0.5,1,2,3,4,6,7,12,24,31,48 and 72 hours.

[0195] Blood samples are frozen at −20° C. immediately after collectionand stored for analysis. Assay is effected by standard cyclosporin Aradioimmunoassay technique employing obtained blood samples in 2μaliquots, assay being effected 2×/sample. Standard curves for the assayare prepared for each individual dog. For characterisation of therelease kinetics, average concentration for each sample, standardvariation, average error and overall average concentration arecalculated.

[0196] Variance analysis (p=1%) indicates a significance difference inaverage-AUC (area under curve) value between compositions A and B, withbio-availability for composition A being superior of that forcomposition B.

[0197] Advantageous bio-availability levels of the same or equivalentorder may be demonstrated in analogous trials to the above employingcompositions of the invention in soft-gelatin capsule form, e.g.compositions prepared in accordance with the preceeding examples 1through 4 or 6 or 7.

[0198] Study II

[0199] Groups of 8 beagle dogs (male, ca. 11-13 kg) are used. Animalsreceive no food within 18 hours of administration of test compositionbut are allowed free access to water until administration. Testcomposition is administered by gavage, followed by 20 ml NaCl 0.9%solution. The animals are allowed free access to food and water threehours after administration of test composition.

[0200] 2 ml blood samples (or 5 ml for the blank) are taken from thevena saphena and collected in 5 ml plastic tubes containing EDTA at −15min. (blank), 30 min., and 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours postadministration. Blood samples are stored at −18° C. pending assay.

[0201] Blood samples are analysed by RIA. Areas under the blood drugconcentration versus time curves are calculated by the trapezoidal rule.Analysis of variance is performed with respect to AUC (area undercurve), Cmax (maximum concentation) and Tmax (time of maximum).

[0202] Calculated average AUC (in ng hr./ml⁻¹) and Cmax (in ng/ml⁻¹)values from individual trial runs together with calculated variation inresponse between test animals receiving the same test composition (CV),demonstrate high bioavailability (AUC and Cmax.) coupled with relativelylow variability in subject response both for AUC and Cmax forcompositions in accordance with the invention, e.g. in accordance withexample 6 above, as compared e.g. with results for the known Sandimmunedrink solution composition (e.g. as described in relation to thefollowing CLINICAL TRIAL) administered at the same Ciclosporin dosagelevel.

[0203] Clinical Trial

[0204] The advantageous properties of the compositions of the inventionon oral administration may also be demonstrated in clinical trials, e.g.performed as follows:

[0205] Trial subjects are adult volunteers, e.g. professionally educatedmales of from 30 to 55 years. Trial groups suitably comprise 12subjects.

[0206] The following inclusion/exclusion criteria are applied:

[0207] Inclusion: Normal screening ECG; normal blood-pressure and heartrate; body weight=50-95 kg.

[0208] Exclusion: Clinically significant intercurrent medical conditionwhich might interfere with drug absorption, distribution, metabolism,excretion or safety; symptoms of a significant clinical illness in thetwo-week pre-trial period; clinically relevant abnormal laboratoryvalues or electrocardiogram; need for concomitant medication during theentire course of the study; administration of any drug known to have awell-defined potential toxicity to a major organ system within theprevious 3 months; administration of any investigational drug within 6weeks prior to entry into the trial; history of drug or alcohol abuse;loss of 500 ml or more blood within the past 3 month period; adversedrug reaction or hypersensitivity; history of allergy requiring drugtherapy; Hep.-B/HIV-positive.

[0209] Complete physical examination and ECG is performed pre- andpost-trial. The following parameters are evaluated within 1-monthperiods pre- and post-trial:

[0210] Blood:—red blood cell count, haemoglobin, hematocrit, erythrocytesedimentation, white blood cell count, smear, platelet count and fastingglucose;

[0211] Serum/plasma—total protein and electrophoresis, cholesterol,triglycerides, Na⁺, K⁺, Fe⁺⁺, Ca⁺⁺, Cl⁻ creatinine, urea, uric acid,SGOT, SGPT, -GT, alkaline phosphatase, total bilirubin, α-amylase;Urine—pH, microalbumin, glucose, erythrocytes, ketone bodies, sediment.

[0212] Creatinine clearance is also determined 1-month prior to trialentry.

[0213] Subjects each receive trial compositions in randomised sequence.Compositions are administered orally, once to a total dose of 150 mgcyclosporin, e.g. Ciclosporin, and at least 14 days are allowed betweeneach administration.

[0214] Administration is performed in the morning after an overnightfast of 10 hrs. with only water allowed. Only caffein-free beverages arepermitted within the 24 hr. period following administration. Subjectsare not allowed to smoke within the 12 hr. period followingadministration. Subjects receive a standardised lunch 4 hrs. followingadministration.

[0215] Blood samples (2 ml) are taken 1 hr. prior to administration andpost-administration at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6,9, 12, 14, 24, 28 and 32 hrs. For determination of creatinine 2 ml bloodsamples are taken immediately prior to administration and at 12, 24 and48 hrs. post-administration. Samples for cyclosporin determination arecollected in two EDTA coated polystyrene tubes (1 ml each) at each timepoint and are deep frozen at −20° C. after gentle agitation. Cyclosporinis assayed in whole blood using RIA with specific and/or non-specificMAB assay—detection limit in both cases ca. 10 ng/ml.

[0216] In trials carried out in accordance with the above protocoll,e.g. comparing the composition of example 6 in hard gelatin encapsulatedform with the current Ciclosporin drink solution (Ciclosporin=50 mg,Labrafil=150 mg, ethanol=50 mg, maize oil=213 mg, in soft gelatinencapsulated form: content end weight=463 mg/dosage) as standard,substantially increased bioavailability levels for the example 6composition are recorded in comparison with the standard as reflected inboth AUC (0-32 hrs) and Cmax values established. In addition, comparisonof variation in whole blood Ciclosporin concentration (as determined byspecific monoclonal RIA) with time following single administration oftest compositions to a Ciclosporin dosage of 150 mg, demonstrates markedreduction in variability of response between all subjects receivingcomposition in accordance with example 1 as compared with that for allsubjects receiving the standard composition.

[0217] Similar or equivalent results may be obtained following oraladministration of other compositions in accordance with the invention,e.g. as herein described in examples 1 through 5 or 7.

1. A pharmaceutical composition comprising: a) a cyclosporin as activeingredient in a carrier medium comprising b) a fatty acid triglycerideand c) a glycerol fatty acid partial ester or propylene glycol orsorbitol complete or partial ester.
 2. A pharmaceutical compositioncomprising a) a cyclosporin as active ingredient in a carrier mediumcomprising b+c) a transesterification product of a vegetable oil withglycerol, propylene glycol or sorbitol.
 3. A composition according toclaim 2 comprising b+c) a transesterification product of a naturalvegetable oil and glycerol or sorbitol.
 4. A composition according toclaim 3 for oral administration.
 5. A composition according to claim 3,wherein (a) is selected from the group consisting of Ciclosporin,(Dihydro-MeBmt)¹-(Val)²--Ciclosporin and (Nva)²-Ciclosporin.
 6. Acomposition according to claim 3, wherein (b+c) is a corn oil, almondoil, ground-nut oil, olive oil or palm oil trans-esterification product.7. A composition according to claim 6, wherein (b+c) is a corn oiltrans-esterification product.
 8. A composition according to claim 3,wherein (b+c) is a trans-esterification product of a vegetable oil andglycerol.
 9. A composition according to claim 3, wherein (b+c) is atrans-esterification product of a vegetable oil and sorbitol.
 10. Acomposition according to claim 3, wherein the amount of free glycerolplus any other free mono- or poly-ol present in (b+c) is less than 10%,preferably less than 5%, by weight.
 11. A composition according to claim3, wherein the amount of mono-glyceride present in (b+c) is ca. 25-50%,preferably 30-45% by weight.
 12. A composition according to claim 8,wherein the amount of free glycerol present in (b+c) is less than 10%,preferably less than 5%, more preferably ca. 4% by weight.
 13. Acomposition according to claim 8, wherein the amount of mono-glyceridepresent in (b+c) is. 35-50% by weight, preferably 40-45% by weight. 14.A composition according to claim 8, wherein the amount of di-glyceridepresent in (b+c) is less than 40% and the amount of tri-glyceridepresent is less than 10% by weight.
 15. A composition according to claim9, wherein the amount of free glycerol plus free sorbitol present in(b+c) is less than 5%, preferably ca. 1-2% by weight.
 16. A compositionaccording to claim 9, wherein the amount of mono-glyceride present in(b+c) is 30 to 40% by weight, preferably ca. 35% by weight.
 17. Acomposition according to claim 12, wherein (b+c) is a corn-oiltrans-esterification product.
 18. A composition according to claim 3additionally comprising: d) a pharmaceutically acceptable solvent ordiluent miscible with (b+c) and reducing, or capable of reducing, theviscosity of (b+c).
 19. A composition according to claim 18, wherein (d)comprises a trans-esterification product of a natural vegetable oiltriglyceride and a polyalkylene poly-ol.
 20. A composition according toclaim 18, wherein (d) comprises ethanol.
 21. A composition according toclaim 15, wherein (d) comprises an esterification product of caprylicacid and caproic acid with glycerol.
 22. A composition according toclaim 3 additionally comprising: e) a pharmaceutically acceptableemulsifying agent.
 23. A composition according to claim 22, wherein (d)comprises a reaction product of a natural or hydrogenated castor oil andethylene oxide.
 24. A composition according to claim 3 in admixture witha pharmaceutically acceptable base material, the admixture being formedas, or capable of being formed into, a solid unit dosage.
 25. Acomposition according to claim 24 wherein the pharmaceuticallyacceptable base material comprises a natural fat, in particular anatural vegetable fat such as cacao fat or cacao butter.
 26. Acomposition according to claim 24 wherein the pharmaceuticallyacceptable base material comprises a chocolate base, for examplecouverture chocolate.
 27. A composition according to claim 1 comprising:a) a cyclosporin as active ingredient in a carrier medium comprising b)a fatty acid triglyceride c) a glycerol fatty acid partial ester orpropylene glycol or sorbitol complete or partial ester, and e′) atenside having an HLB of at least
 10. 28. Composition according to claim27 wherein components (b) and (c) consist or consist essentially of theindividual components of a trans-esterification product of a vegetableoil with glycerol, said composition: i) being free or substantially freeof ethanol; or ii) comprising Ciclosporin or [Nva]2-Ciclosporin ascomponent a); or iii) comprising components (a) and (e′) in a ratio of1: at least 1 p.p.w.
 29. Composition according to claim 27, wherein (a)is present in an amount of from about 2 to about 20% by weight based onthe total weight of components (a) to (c) and (e′) inclusive. 30.Composition according to claim 27 wherein (d) comprises the reactionproduct of a natural or hydrogenated castor oil and ethylene oxide, apolyoxyethylene-sorbitan-fatty acid ester, a polyoxyethylene fatty acidester, a polyoxyethylene-polyoxypropylene co-polymer or blockco-polymer, dioctylsuccinate, di-[2-ethylhexyl]-succinate, aphospholipid, a propylene glycol mono- or di-fatty acid ester or sodiumlauryl sulfate.
 31. Composition according to claim 27 wherein (a). and(e′) are present in a ratio of about 1:1 to 25 p.p.w. [(a):(e)]. 32.Composition according to claim 27 comprising a component (a) and acomponent (e′) as defined in claim 27 and [(b)+(c)] atransesterification product of a vegetable oil and glycerol, propyleneglycol or sorbitol.
 33. Composition according to claim 32 wherein (b)and (c) consist or consist essentially of the individual components (b)and (c) of a component [(b)+(c)] as defined in claim
 32. 34. Compositionaccording to claim 33 wherein (a) and [(b)+(c)] are present in a ratioof about 1:0.75 to 35 p.p.w. [(a):[(b)+(c)]].
 35. Composition accordingto claim 27 comprising at least one ingredient which consists orconsists essentially of a component or components (b) as defined inclaim 27 or of a component or components (c) as defined in claim
 27. 36.Composition according to claim 27 wherein (c) comprises a glycerol fattyacid partial ester or acetylated derivative thereof.
 37. Compositionaccording to claim 27 wherein (b) and (c) are present in a ratio ofabout 1:0.02 to 3.0 p.p.w. [(b):(c)].